Third-space fluid distribution of pemetrexed in non-small cell lung cancer patients

Our plain-English summary of Third-space fluid distribution of pemetrexed in non-small cell lung cancer patients, by P.H. Honoré, S.J. Joensen, M. Olsen, et al (Cancer Chemotherapy and Pharmacology, 2014).

The study

• Authors: P.H. Honoré, S.J. Joensen, M. Olsen, S.H. Hansen, A. Mellemgaard
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2014;74(2):349-57
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aim: Hydrophilic drugs particularly those with low plasma protein binding may accumulate in third-space fluid in the body. Cytotoxic drugs like methotrexate (MTX) cause damage in the tissue, and evacuation of the third-space fluid in pleura is strongly recommended before new dosing. Pemetrexed (PEM) is a multi-targeted antifolate similar to MTX approved for the treatment for malignant pleural mesothelioma and non-small cell lung cancer. Current recommendations for patients receiving treatment with PEM prescribe draining of the pleural fluid. This is based upon the recommendations for MTX and not directly to any specific findings relating to PEM. The recommendations are the same because PEM is an analogue of MTX; the molecular structures and pharmacokinetic parameters are similar. However, since draining the pleural fluid is painful and cancer patient are particularly susceptible to infection subsequently, it is relevant to examine the recommendations for PEM explicitly.

Method: Eight patients treated with a 500 mg/m(2) PEM combined with platinum salt were examined. Plasma samples were first collected in relation to the start of PEM infusion. Thereafter, plasma and pleura samples were taken at various times after drug infusion from each patient; in two patients, sampling was done twice but on different occasions. The quantitative determination of PEM was performed with reversed-phase high-performance liquid chromatography, and sample preparation was performed using protein precipitation with perchloric acid. Pharmacokinetic analysis was performed using a non-compartment method as well a two-compartment model.

Results: The results were calculated from 10 samples taken from eight patients, where data from one patient point were excluded as the patient had impaired renal function, and three samples were reported as below limit of quantification. The plasma PEM pharmacokinetics calculated showed an elimination half-life (t ½ elimination) of 3.2 h and distribution half-life (t ½-distribution) of 6 min. Clearance (CL) was 5.1 L/h, central volume of distribution (V(central)) 23.2 L and peripheral volume distribution (V(peripheral)) 10.6 L, and the area under the curve was 186 μg h/mL. Using non-compartment methods, an elimination half-life of 3.1 h and an apparent CL of 3.2 L/h were measured, whereas an apparent steady-state volume became 14.2 L. The pleura concentrations were only half of simultaneous plasma concentrations, and elimination half-life was 3.15 h.

Conclusion: Pemetrexed is not likely to accumulate in the pleural fluid, and evacuation of fluid might not be necessary. Further investigation is needed to recommend no drainage of the fluid, i.e., in patients with renal impairment.

In plain English

This study measured how the cancer drug pemetrexed moves into fluid that collects around the lungs (pleural effusion). It did not study asbestos exposure or mesothelioma patients. It studied eight patients with non-small cell lung cancer and pleural effusion, two of whom were sampled twice, between March 2012 and June 2013. Patients received 500 mg/m2 of pemetrexed by 10-minute infusion, with cisplatin or carboplatin. The authors pooled 20 plasma and 10 pleural fluid samples. They excluded one patient with slightly impaired kidney function. Pemetrexed levels were higher in plasma than in pleural fluid from 0 to 8 hours. The authors wrote that from 20 to 48 hours pleural levels seemed likely to be higher. Overall pleural exposure was 0.48 times plasma exposure, and the drug left pleural fluid with a half-life of 3.15 hours. The authors concluded that pemetrexed does not seem to accumulate in the pleural cavity, but said a larger study is needed. They noted that their method could not measure the low concentrations present after 20 hours.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Open, non-randomized pharmacokinetic study (measuring drug levels in blood plasma and pleural fluid over time)
• Who was studied: Eight patients with non-small cell lung cancer (adenocarcinoma) and pleural effusion, seven men and one woman, at Herlev Hospital, Copenhagen, Denmark. Two patients were sampled on two occasions. In total, 20 plasma and 10 pleural fluid samples were collected between March 2012 and June 2013.
• Exposure: Pemetrexed, 500 mg/m2 given by 10-minute intravenous infusion, combined with cisplatin or carboplatin. The study involved no asbestos exposure.
• Main results:
  • In these patients, pemetrexed concentrations were higher in plasma than in pleural fluid from 0 to 8 hours. From 20 to 48 hours, the authors wrote it seemed likely that pleural fluid had the higher concentration.
  • Overall drug exposure (area under the curve) in pleural fluid was lower than in plasma, with a pleural-to-plasma ratio of 0.48.
  • The elimination half-life of pemetrexed from pleural fluid was 3.15 hours. The uptake half-life into pleural fluid was 13.9 minutes.
  • The plasma elimination half-life was 3.1 hours (non-compartment model) and 3.2 hours (two-compartment model).
  • Plasma clearance was 3.2 L/h (non-compartment model) and 5.1 L/h (two-compartment model).
  • Plasma concentrations fell rapidly, and no pemetrexed was detected 20 hours after administration.
  • One patient (1.48) was classified as having slightly impaired kidney function and was excluded from the analysis.
  • No clinical adverse effects due to pleural effusion were seen in any patient.
• The authors' conclusion: The authors concluded that pemetrexed does not seem to accumulate in the pleural cavity, and that a larger study is needed to clarify this.
• Limitations the authors state:
  • The analytical method could not measure the low pemetrexed concentrations in pleural fluid and plasma 20 hours after the drug was given.
  • No samples were taken between 12 and 20 hours after administration.
  • Samples from different patients were pooled and analyzed together rather than as full individual profiles.
  • Differences between patients add imprecision to the analysis.
  • The laboratory method met precision criteria but not accuracy criteria, possibly because recovery was low and variable.
  • Plasma sampling was sparse in the first hour after administration, giving a poor description of the drug's distribution phase.
  • The volume of pleural fluid could not be measured reliably.
  • There were too few data points to explain sources of variability, particularly the risk of pleural toxicity in people with impaired kidney function.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Pleura, Antifolate, Pleural Mesothelioma.

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• Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma — S.C. White, H. Anderson, et al. (2000)

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